Purpose :
Retinal neurodegeneration is an early characteristic of several blinding diseases including diabetes, trauma or glaucoma. Neurodegeneration triggers glial activation resulting in inflammation and secondary damage to other retina cell types, which eventually cause visual impairment. Treatments that aimed only at neuroprotection failed clinically. We and others demonstrated the neuroprotective effects of genetic deletion of thioredoxin interacting protein (TXNIP), the negative regulator of the antioxidant thioredoxin system. Here, we examine the impact of TXNIP to the inflammatory secondary damage and visual impairment in a model of ischemic retinopathy.

Methods :
Wild type (WT) and TXNIP knockout (TKO) mice underwent ischemia/reperfusion (IR) injury by increasing intraocular pressure for 40 minutes followed by reperfusion. One group of WT mice received TXNIP antisense oligomers (100µg/2µl) 2-days post ischemic injury. TUNEL assay was used to detect apoptotic cells. Real-time PCR and immunohistochemistry was used to detect TXNIP and activation of Muller glial cells. Vascular degeneration was assessed by trypsin digest, and visual function was assessed by visual cue water-maze test that measures time taken to swim to a fixed platform at 3, 6, 9 days post-injury relative to to base line before injury.

Results :
After 3 days, IR injury induced TXNIP mRNA expression (2-fold) that localized within Muller cells in WT compared to sham-controls. These effects were associated with retinal neurodegeneration (2.3-fold in TUNEL-positive cells), substantial GFAP-glial activation at 3-days that was sustained to 14-days in WT-IR but not in TKO-IR. After 14-days, secondary damage was evident by significant increase in number of acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO compared to sham-controls. Importantly, administration of TXNIP-ASO (2-days post-I/R injury) delayed the development acellular capillaries and significantly improved visual function by day-9.